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1.
During the last decade, interest has grown in the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) in
neurodegeneration, particularly in pathologies such as Alzheimer’s (AD) and Parkinson’s (PD) disease. Evidence from epidemiological
studies has indicated a decreased risk for AD and PD in patients with a history of chronic NSAID use. However, clinical trials
with NSAIDs in AD patients have yielded conflicting results, suggesting that these drugs may be beneficial only when used
as preventive therapy or in early stages of the disease. NSAIDs may also have salutary effects in other neurodegenerative
diseases with an inflammatory component, such as multiple sclerosis and amyotrophic lateral sclerosis. In this review we analyze
the molecular (cyclooxygenases, secretases, NF-κB, PPAR, or Rho-GTPasas) and cellular (neurons, microglia, astrocytes or endothelial
cells) targets of NSAIDs that may mediate the therapeutic function of these drugs in neurodegeneration.
Received 4 December 2006; received after revision 24 January 2007; accepted 23 February 2007 相似文献
2.
Complex diseases arise from a combination of heritable and environmental factors. The contribution made by environmental factors
may be mediated through epigenetics. Epigenetics is the study of changes in gene expression that occur without a change in
DNA sequence and are meiotically or mitotically heritable. Such changes in gene expression are achieved through the methylation
of DNA, the post-translational modifications of histone proteins, and RNA-based silencing. Epigenetics has been implicated
in complex diseases such as cancer, schizophrenia, bipolar disorder, autism and systemic lupus erythematosus. The prevalence
and severity of these diseases may be influenced by factors that affect the epigenotype, such as ageing, folate status, in vitro fertilization and our ancestors’ lifestyles. Although our understanding of the role played by epigenetics in complex diseases
remains in its infancy, it has already led to the development of novel diagnostic methods and treatments, which augurs well
for its future health benefits.
Received 6 December 2006; received after revision 29 January 2007; accepted 15 March 2007 相似文献
3.
Lonez C Legat A Vandenbranden M Ruysschaert JM 《Cellular and molecular life sciences : CMLS》2008,65(4):620-630
The inflammatory effect of unmethylated CpG DNA sequences represents a major obstacle to the use of cationic lipids for in vivo gene therapy. Although the mechanism of CpG-induced inflammatory response is rather well understood nowadays, few solutions
have been designed to circumvent this effect in gene therapy experiments. Our previous work has shown that a refractory state
towards inflammation can be elicited by preinjecting cationic liposomes. Here, we present evidence that diC14-amidine liposomes
confer new anti-inflammatory properties to phospholipids from low-density lipoprotein (LDL) and even to synthetic phospholipids
for which such an observation has not been reported so far. Whereas oxidation of LDL lipids was a prerequisite for any anti-inflammatory
activity, lipid oxidation is no longer required in our experiments, suggesting that cationic lipids transport phospholipids
through a different route and affect different pathways.This opens up new possibilities for manipulating inflammatory responses
in gene therapy protocols but also in a general manner in immunological experiments.
Received 12 November 2007; received after revision 4 December 2007; accepted 4 December 2007 相似文献
4.
Tauopathies are a group of neurodegenerative diseases characterised by intracellular deposits of the microtubule-associated
protein tau. The most typical example of a tauopathy is Alzheimer’s disease. The importance of tau in neuronal dysfunction
and degeneration has been demonstrated by the discovery of dominant mutations in the MAPT gene, encoding tau, in some rare dementias. Recent developments have shed light on the significance of tau phosphorylation
and aggregation in pathogenesis. Furthermore, emerging evidence reveals the central role played by tau pre-mRNA processing
in tauopathies. The present review focuses on the current understanding of tau-dependent pathogenic mechanisms and how realistic
therapies for tauopathies can be developed.
Received 3 December 2006; received after revision 23 February 2007; accepted 20 March 2007 相似文献
5.
The BAG (Bcl-2 associated athanogene) family is a multifunctional group of proteins that perform diverse functions ranging from apoptosis to tumorigenesis.
An evolutionarily conserved group, these proteins are distinguished by a common conserved region known as the BAG domain.
BAG genes have been found in yeasts, plants, and animals, and are believed to function as adapter proteins forming complexes
with signaling molecules and molecular chaperones. In humans, a role for BAG proteins has been suggested in carcinogenesis,
HIV infection, and Parkinson’s disease. These proteins are therefore potential therapeutic targets, and their expression in
cells may serve as a predictive tool for such diseases. In plants, the Arabidopsis thaliana genome contains seven homologs of the BAG family, including four with domain organization similar to animal BAGs. Three members
contain a calmodulin-binding domain possibly reflecting differences between plant and animal programmed cell death. This review
summarizes current understanding of BAG proteins in both animals and plants.
Received 21 November 2007; received after revision 17 December 2007; accepted 2 January 2008 相似文献
6.
Pattern recognition receptors are somatically encoded and participate in the innate immune responses of a host to microbes.
It is increasingly acknowledged that these receptors play a central role both in beneficial and pathogenic interactions with
microbes. In particular, these receptors participate actively in shaping the gut environment to establish a fruitful life-long
relationship between a host and its microbiota. Commensal bacteria engage Toll-like receptors (TLRs) and nucleotide oligomerization
domain (NOD)-like receptors (NLRs) to induce specific responses by intestinal epithelial cells such as production of antimicrobial
products or of a functional mucus layer. Furthermore, a complex crosstalk between intestinal epithelial cells and the immune
system is initiated leading to a mature gut-associated lymphoid tissue to secrete IgA. Impairment in NLR and TLR functionality
in epithelial cells is strongly associated with chronic inflammatory diseases such as Crohn’s disease, cancer, and with control
of the commensal microbiota creating a more favorable environment for the emergence of new infections. 相似文献
7.
Suzuki Y 《Cellular and molecular life sciences : CMLS》2008,65(3):351-353
We have proposed a chemical chaperone therapy for lysosomal diseases, based on a paradoxical phenomenon that an exogenous
competitive inhibitor of low molecular weight stabilizes the target mutant molecule and restores its catalytic activity as
a molecular chaperone intracellularly. After Fabry disease experiments, we investigated a new synthetic chaperone compound
N-octyl-4-epi-β-valienamine (NOEV) in a GM1-gangliosidosis model mice. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced β-galactosidase
activity, reduced the substrate storage, and clinically improved neurological deterioration. We hope that chemical chaperone
therapy will prove useful for some patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
Received 10 October 2007; received after revision 31 October 2007; accepted 6 November 2007 相似文献
8.
The synthesis of acute-phase protein serum amyloid A (SAA) is largely regulated by inflammation- associated cytokines and
a high concentration of circulating SAA may represent an ideal marker for acute and chronic inflammatory diseases. However,
SAA is also synthesized in extrahepatic tissues, e.g. human carcinoma metastases and cancer cell lines. An increasing body
of in vitro data supports the concept of involvement of SAA in carcinogenesis and neoplastic diseases. Accumulating evidence suggests
that SAA might be included in a group of biomarkers to detect a pattern of physiological events that reflect the growth of
malignancy and host response. This review is meant to provide a broad overview of the many ways that SAA could contribute
to tumour development, and accelerate tumour progression and metastasis, and to gain a better understanding of this acute-phase
reactant as a possible link between chronic inflammation and neoplasia.
Received 11 June 2008; received after revision 10 July 2008; accepted 28 July 2008 相似文献
9.
Oshima T Sasaki M Kataoka H Miwa H Takeuchi T Joh T 《Cellular and molecular life sciences : CMLS》2007,64(23):3139-3147
Tight junctions (TJs) create a paracellular permeability barrier. Although reactive oxygen species have been implicated as
mediators of inflammation in inflammatory bowel diseases, their influence on the function of colonic epithelial TJs remains
unknown. Oxidative stress-mediated colonic epithelial permeability was significantly attenuated by a p38 mitogen-activated
protein (MAP) kinase inhibitor, SB203580. Although the amount of TJ proteins was not altered, hydrogen peroxide (H2O2) changed the localization of claudin-4 protein from an NP-40 insoluble fraction to a soluble fraction and from an apical
TJ to lateral membrane. The p38 MAP kinase inactivator Wip1 significantly attenuated phosphorylation of p38 MAP kinase, and
oxidative stress mediated permeability. H2O2-induced changes in claudin-4 localization were abolished by SB203580 pretreatment as well as Wip1-expressing adenovirus infection.
This is the first study to demonstrate that exogenous Wip1 functions to protect oxidative stress-mediated colonic mucosal
permeability and that H2O2-induced claudin-4 dislocalization is abolished by Wip1.
Received 14 June 2007; received after revision 8 October 2007; accepted 8 October 2007 相似文献
10.
Kenji Izuhara Satoshi Nunomura Yasuhiro Nanri Masahiro Ogawa Junya Ono Yasutaka Mitamura Tomohito Yoshihara 《Cellular and molecular life sciences : CMLS》2017,74(23):4293-4303
We found for the first time that IL-4 and IL-13, signature type 2 cytokines, are able to induce periostin expression. We and others have subsequently shown that periostin is highly expressed in chronic inflammatory diseases―asthma, atopic dermatitis, eosinophilc chronic sinusitis/chronic rhinosinusitis with nasal polyp, and allergic conjunctivitis—and that periostin plays important roles in the pathogenesis of these diseases. The epithelial/mesenchymal interaction via periostin is important for the onset of allergic inflammation, in which periostin derived from fibroblasts acts on epithelial cells or fibroblasts, activating their NF-κB. Moreover, the immune cell/non-immune cell interaction via periostin may be also involved. Now the significance of periostin has been expanded into other inflammatory or fibrotic diseases such as scleroderma and pulmonary fibrosis. The cross-talk of periostin with TGF-β or pro-inflammatory cytokines is important for the underlying mechanism of these diseases. Because of its pathogenic importance and broad expression, diagnostics or therapeutic drugs can be potentially developed to target periostin as a means of treating these diseases. 相似文献
11.
Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases
Nitrosative and oxidative stress, associated with the generation of excessive reactive oxygen or nitrogen species, are thought
to contribute to neurodegenerative disorders. Many such diseases are characterized by conformational changes in proteins that
result in their misfolding and aggregation. Accumulating evidence implies that at least two pathways affect protein folding:
the ubiquitin-proteasome system (UPS) and molecular chaperones. Normal protein degradation by the UPS can prevent accumulation
of aberrantly folded proteins. Molecular chaperones – such as protein-disulfide isomerase, glucose-regulated protein 78, and
heat shock proteins – can provide neuroprotection from aberrant proteins by facilitating proper folding and thus preventing
their aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Here,
we present evidence for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.
Received 5 December 2006; received after revision 7 February 2007; accepted 15 March 2007 相似文献
12.
Cationic host defence peptides: Innate immune regulatory peptides as a novel approach for treating infections 总被引:9,自引:0,他引:9
An increase in antibiotic resistance and the emergence of new pathogens has led to an urgent need for alternative approaches
to infection management. Immunomodulatory molecules that do not target the pathogen directly, but rather selectively enhance
and/or alter host defence mechanisms, are attractive candidates for therapeutic development. Natural cationic host defence
peptides represent lead molecules that boost innate immune responses and selectively modulate pathogen-induced inflammatory
responses. This review discusses recent evidence exploring the mechanisms of cationic host defence peptides as innate immune
regulators, their role in the interface of innate and adaptive immunity, and their potential application as beneficial therapeutics
in overcoming infectious diseases.
Received 3 November 2006; received after revision 14 December 2006; accepted 22 January 2007 相似文献
13.
Grounds MD 《Cellular and molecular life sciences : CMLS》2008,65(11):1621-1625
New approaches to understanding and designing treatments for Duchenne muscular dystrophy (DMD) may emerge from two hypotheses
outlined here. The proposal that growing skeletal muscle is more susceptible to necrosis than adult muscle raises the possibility
that less intensive treatments may be sufficient to protect muscles during the adult phase. The second proposal is that a
different balance of cell and molecular events contributes to acute necrosis (e.g. resulting from exercise) compared with
chronic damage of dystrophic muscle. Validation of such differences presents the potential for more specific targeting of
drugs or nutritional interventions to events downstream of the dystrophin deficiency. A deeper understanding of the events
arising as an early consequence of dystrophin deficiency in these two situations may strengthen approaches to therapy for
DMD designed to improve muscle function and the quality of life.
Received 18 December 2007; received after revision 9 January 2008; accepted 25 February 2008 相似文献
14.
Molecular mechanisms of lymphatic vascular development 总被引:8,自引:1,他引:7
Lymphatic vasculature has recently emerged as a prominent area in biomedical research because of its essential role in the
maintenance of normal fluid homeostasis and the involvement in pathogenesis of several human diseases, such as solid tumor
metastasis, inflammation and lymphedema. Identification of lymphatic endothelial specific markers and regulators, such as
VEGFR-3, VEGF-C/D, PROX1, podoplanin, LYVE-1, ephrinB2 and FOXC2, and the development of mouse models have laid a foundation
for our understanding of the major steps controlling growth and remodeling of lymphatic vessels. In this review we summarize
recent advances in the field and discuss how this knowledge as well as use of model organisms, such as zebrafish and Xenopus, should allow further in depth analysis of the lymphatic vascular system.
Received 26 January 2007; received after revision 5 March 2007; accepted 29 March 2007 相似文献
15.
Polycystic kidney diseases (PKDs) represent a large group of progressive renal disorders characterized by the development
of renal cysts leading to end-stage renal disease. Enormous strides have been made in understanding the pathogenesis of PKDs
and the development of new therapies. Studies of autosomal dominant and recessive polycystic kidney diseases converge on molecular
mechanisms of cystogenesis, including ciliary abnormalities and intracellular calcium dysregulation, ultimately leading to
increased proliferation, apoptosis and dedifferentiation. Here we review the pathobiology of PKD, highlighting recent progress
in elucidating common molecular pathways of cystogenesis. We discuss available models and challenges for therapeutic discovery
as well as summarize the results from preclinical experimental treatments targeting key disease-specific pathways.
Received 8 August 2007; received after revision 19 September 2007; accepted 2 October 2007 相似文献
16.
The elongation and termination steps of protein synthesis are controlled by elongation and release factors, respectively.
Elongation factors deliver the aminoacyl tRNA to the ribosomal A site, ensuring the elongation of the nascent polypeptide
chain by one amino acid at a time, while release factors recognize the stop codons and trigger the release of the polypeptide
from the ribosome. Recently, highresolution crystal structures of ribosomes as well as translation factors on and off the
ribosome have contributed a great deal to our understanding of the molecular basis of protein synthesis. This review concentrates
on recent developments in our understanding of the elongation and termination steps of protein synthesis, particularly the
roles of translation factors and their similarities and differences in the eukaryotic cytosol and prokaryotic systems, through
a combination of structural and biochemical studies.
Received 25 October 2007; received after revision 5 December 2007; accepted 7 December 2007 相似文献
17.
Functions and pathologies of BiP and its interaction partners 总被引:1,自引:1,他引:0
J. Dudek J. Benedix S. Cappel M. Greiner C. Jalal L. Müller R. Zimmermann 《Cellular and molecular life sciences : CMLS》2009,66(9):1556-1569
The endoplasmic reticulum (ER) is involved in a variety of essential and interconnected processes in human cells, including
protein biogenesis, signal transduction, and calcium homeostasis. The central player in all these processes is the ER-lumenal
polypeptide chain binding protein BiP that acts as a molecular chaperone. BiP belongs to the heat shock protein 70 (Hsp70)
family and crucially depends on a number of interaction partners, including co-chaperones, nucleotide exchange factors, and
signaling molecules. In the course of the last five years, several diseases have been linked to BiP and its interaction partners,
such as a group of infectious diseases that are caused by Shigella toxin producing E. coli. Furthermore, the inherited diseases Marinesco-Sj?gren syndrome, autosomal dominant polycystic liver disease, Wolcott-Rallison
syndrome, and several cancer types can be considered BiP-related diseases. This review summarizes the physiological and pathophysiological
characteristics of BiP and its interaction partners.
Received 20 November 2008; received after revision 09 December 2008; accepted 12 December 2008 相似文献
18.
Cell adhesion molecules (CAMs) have been implicated in the control of a wide variety of cellular processes, such as cell adhesion,
polarization, survival, movement, and proliferation. Nectins have emerged as immunoglobulin-like CAMs that participate in
calcium-independent cell-cell adhesion by homophilic and heterophilic trans-interactions with nectins and nectin-like molecules. Nectin-based cell-cell adhesion exerts its function independently or
in cooperation with other CAMs including cadherins and is essential for the formation of intercellular junctions, including
adherens junctions, tight junctions, and puncta adherentia junctions. Nectins cis-interact with integrin αvβ3 and platelet-derived growth factor receptor and facilitate their signals to regulate the formation and integrity of intercellular
junctions and cell survival. Nectins intracellularly associate with peripheral membrane proteins, including afadin and Par-3.
This review focuses on recent progress in understanding the interactions of nectins with other transmembrane and peripheral
membrane proteins to exert pleiotropic functions.
Received 27 June 2007; received after revision 14 August 2007; accepted 12 September 2007 相似文献
19.
J. Fitter 《Cellular and molecular life sciences : CMLS》2009,66(10):1672-1681
Most of fundamental studies on protein folding have been performed with small globular proteins consisting of a single domain.
In vitro many of these proteins are well characterized by a reversible two-state folding scheme. However, the majority of proteins
in the cell belong to the class of larger multi-domain proteins that often unfold irreversibly under in vitro conditions. This makes folding studies difficult or even impossible. In spite of these problems for many multi-domain proteins,
folding has been investigated by classical refolding. Co-translational folding of nascent polypeptide chains when synthesized
by ribosomes has also been studied. Single molecule techniques represent a promising approach for future studies on the folding
of multi-domain proteins, and tremendous advances have been made in these techniques in recent years. In particular, fluorescence-based
methods can contribute significantly to an understanding of the fundamental principles of multi-domain protein folding.
Received 3 December 2008; accepted 23 December 2008 相似文献
20.
Yasuda O Takemura Y Kawamoto H Rakugi H 《Cellular and molecular life sciences : CMLS》2008,65(3):354-358
Aspirin exerts anti-thrombotic action by acetylating and inactivating cyclooxygenase-1, preventing the production of thromboxane
A
2 in platelets. Through this inhibition of platelet function, aspirin is considered as a preventative of ischemic diseases
such as coronary and cerebral infarction. However, many studies have revealed that aspirin has other beneficial actions in
addition to its anti-platelet activity. For example, aspirin may confer some benefit against colorectal cancer. Here, we discuss
the involvement of inflammation in atherosclerosis and how aspirin exerts its beneficial actions in atherosclerotic diseases
and cancer.
Received 30 September 2007; received after revision 31 October 2007; accepted 6 November 2007 相似文献